Expression of Slow Skeletal Troponin I in Adult Mouse Heart Helps to Maintain the Left Ventricular Systolic Function During Respiratory Hypercapnia

Urboniene, Dalia; Dias, Fernando Augusto Lavezzo; Peña, J; Walker, Lori A.; Solaro, R. John; Wolska, Beata M.

doi:10.1161/01.res.0000173849.68636.1e

Cited by 39 publications

(34 citation statements)

References 43 publications

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“…Importantly, even LV IVRT was not significantly different in 12-day-old cTnI Ϫ/Ϫ and wild-type littermates despite expressing different TnI isoforms. This observation is consistent with studies of adult mice overexpressing ssTnI in the heart, which also showed few relaxation abnormalities by echocardiography (35).…”

Section: Discussionsupporting

confidence: 91%

Progressive troponin I loss impairs cardiac relaxation and causes heart failure in mice

Liu

Zhang³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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XP. Progressive troponin I loss impairs cardiac relaxation and causes heart failure in mice. Am J Physiol Heart Circ Physiol 293: H1273-H1281, 2007. First published May 25, 2007; doi:10.1152/ajpheart.01379.2006.-Cardiac troponin I (TnI) knockout mice exhibit a phenotype of sudden death at 17-18 days after birth due to a progressive loss of TnI. The objective of this study was to gain insight into the physiological consequences of TnI depletion and the cause of death in these mice. Cardiac function was monitored serially between 12 and 17 days of age by using high-resolution ultrasonic imaging and Doppler echocardiography. Two-dimensional B-mode and anatomical M-mode imaging and Doppler echocardiography were performed using a high-frequency (ϳ20 -45 MHz) ultrasound imaging system on homozygous cardiac TnI mutant mice (cTnI Ϫ/Ϫ ) and wild-type littermates. On day 12, cTnI Ϫ/Ϫ mice were indistinguishable from wildtype mice in terms of heart rate, atrial and LV (LV) chamber dimensions, LV posterior wall thickness, and body weight. By days 16 through 17, wild-type mice showed up to a 40% increase in chamber dimensions due to normal growth, whereas cTnI Ϫ/Ϫ mice showed increases in atrial dimensions of up to 97% but decreases in ventricular dimensions of up to 70%. Mitral Doppler analysis revealed prolonged isovolumic relaxation time and pronounced inversion of the mitral E/A ratio (early ventricular filling wave-to-late atrial contraction filling wave) only in cTnI Ϫ/Ϫ mice indicative of impaired LV relaxation. cTnI Ϫ/Ϫ mouse hearts showed clear signs of failure on day 17, characterized by Ͼ50% declines in cardiac output, ejection fraction, and fractional shortening. B-mode echocardiography showed a profoundly narrowed tube-like LV and enlarged atria at this time. Our data are consistent with TnI deficiency causing impaired LV relaxation, which leads to diastolic heart failure in this model. damaged relaxation; echocardiography; Doppler analysis THE CONTRACTILE SARCOMERIC PROTEINS consist of a highly ordered arrangement of myosin thick filaments, actin thin filaments, and associated proteins, such as the troponin-tropomyosin complex. Contractile sarcomeric protein mutations, truncations, and deletions have been identified for various cardiac disorders in humans and experimental animals (8,16,18,23,25,28

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Section: Discussionsupporting

confidence: 91%

Progressive troponin I loss impairs cardiac relaxation and causes heart failure in mice

Liu

Zhang³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…We chose the slow skeletal isoform for these studies inasmuch as it is naturally expressed in the embryonic/neonatal period. Hearts of TG-ssTnI mice had slower relaxation kinetics, depressed effects of β-adrenergic stimulation [8], and protection against acidosis [9,10] and ischemia/reperfusion injury [11]. All of these properties are properties of preparations from neonatal rat hearts, and indicated that the special cardiac function in the neonatal period is importantly controlled by the isoform of TnI.…”

Section: Specific Modifications In Troponin I Affect the Dynamics Andmentioning

confidence: 99%

The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation

Solaro

Rosevear

Kobayashi

2008

Biochemical and Biophysical Research Communications

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We review development of evidence and current perceptions of the multiple and significant functions of cardiac troponin I in regulation and modulation of cardiac function. Our emphasis is on the unique structure function relations of the cardiac isoform of troponin I, especially regions containing sites of phosphorylation. The data indicate that modifications of specific regions cardiac troponin I by phosphorylations either promote or reduce cardiac contractility. Thus, a homeostatic balance in these phosphorylations is an important aspect of control of cardiac function. A new concept is the idea that the homeostatic mechanisms may involve modifications of intra-molecular interactions in cardiac troponin I. KeywordsCardiac; Sarcomeres; Adrenergic stimulation; Mechanics; Kinases; Phosphatases In the time since the troponin discovery and naming by the laboratory of Setsuro Ebashi [1], there has been a constant stream of evidence indicating the substantial role of modifications in cardiac troponin (cTn) as a critical control element in the body's response to physiological stressors such as the hemodynamic demands of exercise. It is now widely recognized that regulatory processes at the level of the sarcomeres and the hetero-trimeric Tn complex involve not only the reception of Ca 2+ by cTnC, but also transduction of this Ca-binding signal by cTnI and cTnT [2,3]. Multiple interactions of cTnI and cTnT with actin and tropomyosin (Tm) control the number and kinetics of interactions of cross-bridges with the thin filament. Our focus here on cTnI serves to highlight the significant impact of modifications in the function of Tn in working cardiac myocytes and in the integrated physiological responses to exercise, which we have reviewed previously [4,5]. Evidence summarized below indicates that phosphorylation of cTnI by adrenergic signaling cascades is an indispensable control mechanism in matching cardiac output to venous return and myocyte dynamics to heart rate. Specific modifications in troponin I affect the dynamics and intensity of the heart beatElucidation of the function of an N-terminal extension of ~30 amino acids with sites (Ser-23, Ser-24) of phosphorylation by protein kinase A (PKA), not present in the fast skeletal (fsTnI) or slow skeletal isoforms (ssTnI), provided the first evidence that cTnI may have a special role * Corresponding

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“…Compared with controls, ssTnI-TG myofilaments are more sensitive to Ca 2ϩ and thus provide an animal model with myofilaments that are constitutively sensitized to Ca 2ϩ . Hearts of these mice demonstrate a remarkable resistance to acidosis, 21 sepsis, 22 and ischemiareperfusion injury. 23 There is evidence that a difference in a single amino acid (His/Ala) in ssTnI versus cTnI at position 162 is responsible for these functional differences.…”

Section: Targeting Ctni-actin Interactionsmentioning

confidence: 99%

Mechanisms and Use of Calcium-Sensitizing Agents in the Failing Heart

2006

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Expression of Slow Skeletal Troponin I in Adult Mouse Heart Helps to Maintain the Left Ventricular Systolic Function During Respiratory Hypercapnia

Cited by 39 publications

References 43 publications

Progressive troponin I loss impairs cardiac relaxation and causes heart failure in mice

Progressive troponin I loss impairs cardiac relaxation and causes heart failure in mice

The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation

Mechanisms and Use of Calcium-Sensitizing Agents in the Failing Heart

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